Ring closure of aromatic compounds with the aid of hydrofluoric acid



Patented Sept. 26, 1939 UNITED STATES RING CLOSURE OF AROMATIC COMPOUNDS WITH THE AID OF HYDROFLUORIC ACID No Drawing. Application September 30, 1936, Serial No. 103,350

11 Claims. (01. 260-4351) This invention relates to the synthesis of organic compounds. More particularly, this in'- vention relates to an improved method for ringclosing organic compounds of the type which are adapted to form aclosed ring by the action of acidic dehydrating agents. Typical examples of such synthesis are the ring closure of orthobenzoyl-benzoic acidderlvatives to give anthraquinone compounds; the ring-closure of diphenyl methane ortho carboxylic acid compounds to the corresponding anthrones; and the ring closure of diaraylamine-ortho-carboxylic acid compounds to acidones. Further examples, illustrating the full scope of this invention, are given in the discussion below.

It is an object of this invention to provide an improved process for effecting ring-closures, whereby to avoid undesirable side reactions such as oxidation, reduction, sulfonation, or halogenation. It is a further object of this invention to provide a process for ring-closure which is of wide applicability, and is characterized by simplicity of procedure and economy of materials.

' Other and further important objects of this invention will appear as the description proceeds. These objects are accomplished, according to our invention, by the simple expedient of employing hydrofluoric acid as the ring-closing agent. More particularly, we proceed as follows: An organic compound potentially capable of being converted to a cyclic structure is dissolved or suspended in concentrated hydrofluoric acid and heated, if necessary, at atmospheric or superatmospheric pressure in anqautoclave until ringclosure has taken place. The product may be recovered by pouring'the reaction mixture into water, or distilling ofl the excess hydrofluoric acid and recovering the product from the residue.

We have discovered that concentrated hydrofluoric acid possesses the valuable quality of promoting ring-closure of such organic compounds which are adapted to form a ring when acted upon by acidic dehydrating agents, and possesses moreover additional qualities which adapt it excellently to the reaction under discussion. Hitherto it has been customary in general to employ concentrated or fuming sulfuric acid, aluminum chloride, phosphorus pentoxide, phosphorus pentachloride, or halogen sulfonic acids for the ring-closure of the open chainsof various classes of organic compounds. With these reagents, however, undesirable side reactions often accompany the ring-closure to such an extent that the yield of desired product is seriously if not completely inhibited. Beta naphthyl thioglycolic acid, for instance, cannot be ring-closed satisfactorily in concentrated or fuming sulfuric without sulfonation in the naphthalene ring. The production of anthrones by the ringclosure of diphenyl-methane-2-carboxylic acids in sulfuric acid is accompanied by partial oxidation of both the starting material and the finished anthrone to anthraquinone derivatives. Aluminum chloride and phosphorus pentoxide yield tars containing only small quantities of anthrones.

Now, we have found that hydrofluoric acid is free from these defects, and accomplishes these ring-closures without reacting with the compound'itself, either as an oxidizing or reducing agent. or by substitution in the ring system. Diphenylmethane-2-carboxylic acid, for instance, when ring-closed in hydrofluoric acid gives a quantitative yield of anthrone of high purity.

The ring-closure of beta naphthyl thioglycolic acid proceeds without sulfonation or oxidation to give good yields of 2,1-naphthioindoxyl. Other cases likewise exhibit marked advantages.

Moreover, anhydrous hydrofluoric acidis one of the best solvents for high-molecular-weight ring-systems. Therefore, ring-closure of compounds such as -1,5-dianilido anthraquinone- 2',2"-dicarboxylic acid proceeds smoothly and rapidly as a single phase reaction, and gives a .practically, theoretical yield of l,2,5,6-anthraquinone diacridone. Alpha naphthoyl-2-benzoic acid likewise ring-closes quantitatively to 1,2-

PATENT f OFFICE benz-anthraquinone of high purity, whereas the same reaction if carried out in sulfuric acid is accompanied by sulfonation and low yields of the desired product.

The problem of recovery is also very simple with hydrofluoric acid. In most cases the reaction product crystallizes out when the reaction mass is diluted with cold water. A simple filtration then separates the desired reaction product from the excess hydrofluoric acid employed. In

of the hydrofluoric acid employed. Thus, with anhydrous or nearly anhydrous hydrofluoric acid, reaction in many cases may-proceed at ordinary temperature within a very short time, while the use of relatively dilute, aqueous hydrofluoric acid may require heating and stirring for a considerable length of time. Aside from this time factor, however, any concentration of hydrofiuoricacid, down to about 43%, may be employed- In the following discussion, as well as in the claims, the

phrase concentrated hydrofluoric acid should be construed as referring to hydrofluoric acid or" from 43.2% to 100%, the lower limit being selected at 43.2% for the reason that at this concentration hydrofluoric acid forms a constant boiling mixture with water (boiling point 111 C.).

Ring-closure would probably take place also in solutions much weaker than 43.2% if elevated temperature were employed, but two factors enter-here which render the process impractical, namely: With lower concentrations the rate of reaction is slow, and dilute aqueous hydrofluoric acid is extremely corrosive and it would be hard to find suitable apparatus to withstand this reaction especially at elevated temperature and pressure.

With concentrated hydrofluoric acid, the last 'mentioned problem is less keen. For concentravapor pressure of the hydrofluoric acid at the operating temperature, maintained by a sealed system iortemperatures above 20 C. However, the pressure may, if desired, be augmented by the addition of materials having a higher vapor pressure than hydrofluoric acid; or, on the contrary, the partial pressure of the hydrofluoric acid may be reduced by the addition of substances such as toluene, sodium fluoride, etc., which are inert to the compound being ring-closed, and

which have vapor pressures lower than hydro- As regards temperature, we prefer to operate in the range 20 to 150 C., but the ring-closing action of concentrated hydrofluoric acid is'not confined to these limits. Practical considerations exclude other ranges; for instance, below 0., ring-closure proceeds very slowly, and at temperatures above 150 C. many organic compounds are decomposed. Aside from such practicalfactors, however, ring-closure may take place to more or less extent in anhydrous hydrofluoric acid from the freezing point, --83 C., to the critical temperature, 230 C.

The same conditions of temperature apply to dilute hydrofluoric acid, that is, the operating range extends from the freezing point to the critical temperature of any given mixture, but we prefer to use the temperature range 20 to 150 C.

In the specific examples given below, we prefer to use a ratio of 2 to parts of hydrofluoric acid to each part of starting material, but these limits are arbitrary. The amount of hydrofluoric acid 'used, above the amount necessary to bring about ring-closure, will be deteed by operating conditions, that is, the fluidity of the charge,

facilities for recovery of the excess hydrofluoric acid, etc.

Without limiting our invention to any particular procedure, the following examples are given to illustrate our preferred mode of operation. Parts mentioned are by weight.

Exsiurta 1 Anthrone into a copper vessel chilled in an ice pack are charged 2'! parts of liquid, anhydrous hydrofluoric acid and parts of diphenyl methane-2- carboxylic acid (melting point 115 0.). The mixture is allowed to warm to -25 C., and after keeping it one hour at this temperature, the reaction mass is poured into ice. The white precipitate is filtered off, washed acid-free, extracted with 100 parts of 10% sodiumcarbonate solution; filtered, washed alkali free and dried.

A 93% yield of crude anthrone melting at 152-156 C. is obtained.

EXAMPLE 2 Antizrone Into a steel pressure vessel, chilled in an ice pack, are charged 83 parts of 80% hydrofluoric acid and 21 parts of diphenyl methane-Z-carboxylic acid. The mass is heated to (110 C. under its own pressure, and held at tlus temperature for two hours. The reaction mass is then chilled in an ice pack and poured out into ice. The flocculent white precipitate is filtered off, washed acid free and dried. A quantitative yield of anthrone melting at 149 -154 is obtained.

EXAMPLE 3 2-methyl anthraquinone Into a steel pressure vessel, chilled in an ice pack, are charged 68 parts of liquid anhydrous hydrofluoric acid and 20 parts of '-mcthyl benzophenone-Z-carboxylic acid. The mixture is heated under autogenous pressure to 100 C. and held at this temperature for two hours. After chilling in an ice pack, the reaction mixture is poured into ice. quinone is filtered oil, washed aciddree, digested in 100 parts of 10% sodium carbonate solution; filtered, washed alkali-free and dried. An 80% yield of Z-methyl anthraquinone is obtained. It melts at 175.5 to 1'76.0 C. after crystallization from alcohol. w

, EXAMPLE 4 Z-chlor anthraqm'none Into a nickel borr'o, chilled in an ice pack, are charged 70 parts cit liquid, anhydrous hydrofluoric acid and 28 parts of 4'-chloro-2-benzoyl benzoyl chloride (prepared by treating 4'-chloro-benzophenone-tZ-carboxylicacid with thionyl chloride; melting range 65-68 C.). The mass is heated to 130 C. under autogenous .pressure and held at this temperature for two hours. It is then chilled thoroughly in an ice pack, and poured into ice. The greyish yellow precipitate is flltered ofi", washed acid-free, extracted with 200 The crude Z-methyl anthraxparts of 10% sodium carbonate; filtered, washed alkali-free and dried. A good yield of 2-chlortained.

anthraqtinone melting at 205"-206 C. is 'ob EXAMPLE 5 Ring-closure of 4'-chloro-2-benzoyl-benzcmide Into a nickel bomb, chilled in an ice pack, are charged parts 01. liquid, anhydrous hydrofluoric acid and 20 parts of 4'-chloro-2-benzoylbenzamide (synthesized from 4'-chloro-benzoyl-.- 2-benzoyl chloride and aqueous ammoniaymeiting range 176-181 0.). The mass is heated to 130 C. under its own pressure and held at this temperature for two hours. It is then chilled in an ice pack and poured out into ice. After allowing to stand for several hours, the precipitate is filtered oil, washed acid-free, digested in 200 parts of 10% sodium carbonate solution; filtered, washed free oi alkali and dried. The product is 2-chloro-anthraquinone of good quality.

Exsurm: 0

- Ring-closure. of methyl-f-chloro-il-benzoylbenzoate Into a nickel bomb, chilled in an'ice pack. are charged 80 parts of liquid, anhydrous hydrofluoric acid and 27.5 parts of methyl-4'-chloro-2- benzoyi-benzoate (prepared by treating 4'-chloro- 2-benzoyl benzoyl-chloride with methyl alcohol;

melting range 109-110 C.) v The mas is heated to 130 C. under autogenous pressure, and held at this temperature for two hours. It is then chilled in an ice pack and poured into ice. The brown tar which precipitates out crystallizes on standing for several hours. It is filtered oi! and washed acid-free. The crude product is extracted with 200 parts 01 10% sodium carbonate solution:

filtered. washed alkali-tree and dried. 'The unreacted methyl-4'-chloro-benzoyl-2-=benzoate is removed by extracting with boiling methyl alcohol. A good yield of 2-chloro-anthraquinone is obtained.

Exmu 7 Alphanaphthoyl-Z-benzoic acid -v 1,2-benz-anthraduinone Into a steel autoclave, chilled with ice, are charged120 parts of liquid, anhydrous hydrofluoric acid and parts of alpha naphthoyl-2- benzoic acid (M. P. 165-167 0.). Heat to 100 C. under autogenous pressure and hold at this temperature for two hours. Chill and pour the 3 reaction mixture into ice. Filter on the dark nooo l, 5 dianilino anthraquinone-f-f', ,----t 1, 2, 5

green, flocculent product, wash acid-free, and extract with 500 parts of 5% sodium carbonate solu- .tion at 90-95 C. Filter, wash free of alkali and dry. A 'quantitative yield 01' 1,2 benzanthraquinone is obtained. The melting range of the crude material; 150-154 C. may be raised to 165- 167 C. by recrystallizing once from glacial acetic acid.

. Enron 8 Anthraquinone-Z-mlflnic acid 'Into a nickel pressure vessel, chilled with ice are charged parts or liquid, anhydrous hydrofiuoric acid and 15 parts or the disodium salt of '4'-sulio-2-benzoyl-'benzoic acid. Heat to 130 C. and hold at this temperature for two hours. Chill thoroughly and pour into ice. A portion of the product may be recovered directly by filtering and the fraction remaining in solution may be recovered by salting out with ammonium fiuoride or by adding a potassium salt, such as potassium chloride. A Good yield of anthraquinone-2- sodium-sulionate is obtained.

Exams: 9

2'-nitro-diphenyleifiine-2- l-nitromcidrone carboxyll Into a steel autoclave, chilled to 0 C., charge parts of liquid, anhydrous hydrofluoric acid and 24 parts of 2'-nitro-diphenylamine-Z-carboxylic acid, melting range 213-215 C. Heat to C.- under autogenous pressure and hold at this temperature for two hours. After chilling to 0 C., pour the reaction mixture into ice. 'Filter,

.wash acid-free, extract with 200 parts of 10% sodium carbonateso'lution at 90-95 (2.; filter, wash free of alkali and dry. A nearly quantitative yield of l-nitro-acridone melting at. 256- 258 C. is obtained. 1

Emu 10 1, 2, 5, 6 anthraquinone-diacqidone; Color Index No. 1163 anthnquinone dialldone 6 dicarboxylic acid (indantbrane Violet IN) Into a steel bomb, chilled in an ice pack, charge 110 parts of liquid, anhydrous hydrofluoric acid and 30 parts 1,5-dianilino-anthraquinone-2'-2", dicarboxyllc acid. Heat to 130 C. and hold-at this temperature for four hours. Chill and dilute the charge in ice. Filter 011 the purple precipitate, wash acid free and dry. A theoretical yield or 1,2,5,6 anthraquinone diacridone is obtained.

Exam 11 COOH l-anilino-anthraquinone-Z- carboxylic acid carboxylic acid Into a steel 'pressure vessel, chilled with ice,

charge 110 parts or liquid, anhydrous hydrofluoric acid and parts of l-anilino-anthraquinone-Z-carboxylic acid. Heat to 100 C. un-

der pressure and holdat this temperature for four hours. Chill and pour the reaction mixture into ice. Filter 01! the deep red precipitate, wash acid free and dry. The 92% yield of crude product may be purified by, dissolving in a large volume of hot, dilute sodium precipitating in a mixture oi ice and excess hydrochloric acid. The product is insoluble in all but the higher boiling solvents; gives a red-brown color in concentrated sulfuric acid; and vats in warm, alkaline sodium hydrosuliite. These properties of the product correspond to l-acridineanthraquinone-2-carboxylic acid as described in Germ. Pat. No. 262,469 (Friedlaender 31,687).

. Exaurr: 12 Rina rclosure of I-beta-naphthul-amind anthraquinone-Z-carboxulic acidl-be'ta naphthyl amino anthraquinone-Z-carboxylic acid under conditions similar to those described in Example 11 gives a high yield of material possessing properties closely resembling 1- acridine-anthraquinone-2 carboxyiic described in Example 11.

- Exnrru: 13

' Hm, I l-antliraquinonyl-hydrazine Pyrarole anthronc v Into a steel bomb, chilled in an ice pack, charge 110 parts of liquid, anhydrous hydrofluoric acid and 36 parts of 1-anthraquinonyl-hydrazine,

melting at 233-235 C. Heat to 100 C. under pressure and hold at this temperature for two hours. Chill and pour the charge into ice. Fil ter the brown-precipitate and wash acid free. A high yield (86%) of pyrazole-anthrone, melting at 247-250 C., is obtained. The product yields alight brown color with strong, yellow fluores cence in concentrated suliuricacid. A known sample 01 pyrazole-anthrone melted at 248-252 i is C. and showed similar color in concentrated sul- O 1-acridine-cnthraquinone-2- hydroxide and re- J Betamaphthyl-tbioglycolio acid 2, l-naphthio-indoxyl Into an 18-8 stainless-steel bomb, chilled in an ice pack, charge '70 parts of liquid, anhydrous hydrofluoric acid and 20 parts of beta-naphthylthioglycolic acid, melting range 91-92.5 C.

Heat to 98-99 C. and hold at this temperature for fifteen minutes. Chill at once and-pour onto ice (approximately-300 parts) Filter, wash acid- 1 free, and either dry the crystals or. oxidize the g paste directly in the usual manner, to bisnaphthothiophene-indlgo. A 54% yield of crude color is obtained by the oxidation of the crude thioindoxyl.

Essentially the'same results are obtained when the charge is heated at 30 C. for six hours in a nickel bomb. The crude thio-indoxyl has a melting range of 98 to 104 C.

' Exmta 15' Ringwlosure of 3',4'-diamino-2-benzoz l benzoic (Probable reaction) Into a steel pressure vessel, chilled with ice, charge 40 parts of liquid, anhydrous hydrofluoric acid and 10 parts 0! 3,4'-diamino'-2-benzoylbenzoic acid (M. P. 190 C.) f Heat to 100 C. and

hold at this temperature for two hours. Chill thoroughly and pour into ice. Filter of! the light brown product, wash acid-free and dry. The product is insoluble in cold dilute alkali, but slowly dissolves in dilute, boiling sodium hydroxide. A small amount of authraquinone bodies is present. The predominating product is probably an internal lactam of 3',4 -diamino-2-benzoyl benzoic acid (Br.- Pat. 160. 22,440 or 1912) EXAMPLE 16 Rina-closure o1 y-GminD-f-CMOTO-Z-UWOIJF- became acid (Probablereaetion) I Into a steel bomb, chilled in an ice pack, charge parts of liquid anhydrous hydrofluoric acid and 20 parts of 3'-amino-4'-ch1oro-2-'-benzoyl benzoic acid. Heat to 100 C. under pressure and hold at this temperature two hours. Chill thoroughly and pour onto ice. 'Filter oil the grey precipitate, wash acid free and dry. The product is insoluble in warm sodium carbonate or dilute sodium hydroxide. Prolonged boiling in dilute sodium hydroxide dissolvesthe product, however.

Very little vat formation takes place in warm,

alkaline sodium hydrosulfite solution. The product is probably an internal lactam of 3-amino- 4'-chloro-2-benzoyl benzoic acid.

The advantages of our invention will now be 4 readily understood. Hydrofluoric acid as a ringclosing agent provides the following advantageous conditions:

1. It is anon-oxidizing and non-reducing medium.

2. It is a powerful dehydrating agent.

3. Anhydrous hydrofluoric. is one of the best solvents for high molecular weight organic compounds, especially the complex vat dyestufls.

4. Hydrofluoric acid may be recovered by simple distillation at low temperature (boiling point at atmospheric pressure is 203 0.). 5. Ease of manipulation. No special equipment is necessary. An ordinary, high-pressure, steelautoclave with brine-jacketed .steel condenser is adequate.

6. The use of concentrated hydrofluoric eliminates objectional sulionation which is encountered in the use of concentrated .sulfuric acid, oleum or halogen sulionic acids as ring-closing agents.

Concentrated hydrofluoric acid provides the best medium discovered to date for the ring closure of compounds which are easily oxidized, both in the initial stage and the finished prod- .uct stage, e. g., diphenylmethane-2-carboxyiic acid. Since organic compounds in general are very soluble in anhydrous hydrofluoric "acid, ring-closure proceeds smoothly and rapidly as a single phase reaction. When the reaction is finished, the charge may be run into ice and the product isolated by filtration; or better, the hydrofluoric acid may be simply distilled oil and reused. In cases where water is the by-product' only a very small amount of hydrofluoric acid is lost to the process as a constant boiling mixture containing 43% HzFz.

It will be observed that although we referred in the introduction to organic compounds adapted to form a closed ring under the action of acidic dehydrating agents, our invention is by no means restrictedto ring-closures by the elim ination of 1120. On the contrary, as illustrated by the above specific examples, hydrofluoric acid may be successfully employed as a ring-closing agent in many cases where the elements split ofl are those of hydrochloric acid (Example 4), ammonia (Example 5), alkali metal hydroxide (Example 8) or a lower alcohol (Example 6). This is particularly true when one deals with the ringclosures of diaryl-methane-ortho-carboxylic acids and diaryl-ketone-ortho-carboxylic acids. To put it in different words, according to our observations hydrofluoric acid will operate successfully as ring-closing agent whether the side chain involved in the ring-closure is 'a free carboxylic acid group or a functional derivative thereof such as metal salt, alkyl ester, amide or chloride.

- In this particular respect,- hydrofluoric acid is not singular, since concentrated suliuric acid and other acidic dehydrating agents are likewise capable of ring-closing ortho-benzoyl-benzoic acid derivatives regardless whether the carboxylic acid group is free or in the form oi a functional derivative of the same. It will be understood-therefore that where we speak oi acidic dehydrating agents in the claims below, we are not attempting to limit this invention to the case of splitting off water, but are merely trying to identify a group of reagents which are normally employed for ring-closure and which by their capacity of eifectlng ring-closure define the organic materials to which this invention is applicable. V

It will be understood that although we reported above a number of specific procedures with great particularity, many variations and modifications are permissible inour preferred mode of procedure, without departing from the spirit of this invention. 4

We claim:

1. In the process of ring-closing an aromatic compound of the type which is adapted to form a closed ring by treatment with acidic dehydrating agents, the improvement which comprises use of a proportion of concentrated hydrofluoric acid suflicient to eflect ring-closure and leave an acid residue containing not less than 43% strength hydrofluoric acid.

2. In the process of ring-closing an aromatic compound of the type which is adapted to form a closed ring by treatment with acidic dehydration agents, the improvement which comprises employing an amount of hydrofluoric acid suflicient ,to eflect ring-closure and leave an acid residue containing not less than 43% strength hydrofluoric acid.

I 3. A process according to claim, 2 in which the pound ofthe type adaptedtoform a closed ring by the elimination of water, which comprises treating such compound withsufllcient concentrated hydrofluoric acid to efiect ring-closure and leave an acid residue containing not less than 43% strength hydrofluoric acid.

6. In a process of synthesizing an organic compound by eliminating the elements of water from a related compound, with the formation of a closed ring, the improvement which comprises effecting the elimination and ring-closure by the aid of an amount ofconcentrated hydrofluoric acid sufficient to effect ring-closure and leave a residual acid of not less than 43% strength.

7. The process of ring-closing an organic com pound of the general formula wherein Y is amember of the group consisting of CO, CH: and NH and Z is a member of the group consisting of'the carboxylic acid .radical and functional derivatives thereof. which comprises reacting said compound with a proportion of concentrated hydrofluoric acid sufficient to eflect ring-clo'sureand leave an acid residue containing not less than 43% strength hydrofluoric acid.

8. The process fof producing an anthrone com- 1 pound, which comprises rin-closing a 'correspending diphenyl-methane-o-carboxyiic acid compound by the aid of concentrated hydrofluoric acid in amount suflicient to effect ring-closure and leave an acid residue of at least 43% strength hydrofluoric acid. a

9. In the process oi ring-closing a diaryl-r methane compound which possesses an unsubstitutedprtho position on one aryl radical and a reactive ortho carboxyl' group on the other aryl radical, the improvement which comprises effecting the ring-closure by the aid of -9. proportion of concentrated hydrofluoric acid suflicient to effect ring-closure and leave van acid residue of at least 43% strength hydrofluoric acid.

10. The process of producing a cyclic organi ketone compound, which comprises ring-closing a corresponding ortho-benzoyi-benzoic acid compound in a medium consisting of concentrated hydrofluoric acid in amount suflicient to effect ring-closure and leave an acid residue of at least 43% strength hydrofluoric acid.

11. The process of producing an acridone compound which comprises ring-closing a diphenyie a'mine-2-carboxyiic acid by the aid of concentrotted-hydrofluoric acid in amount sufllcient-to eflect ring-closure and leave an acid residue of at least 43% strength hydrofluoric acid. 

